Post-Herpetic Neuralgia (PHN) remains a common, exceedingly painful and debilitating complication of Herpes Zoster that is difficult to treat. Zostr and PHN occur when the herpesvirus varicella-zoster virus (VZV) reactivates from latency within host sensory neurons, and up to one third of adults worldwide are at risk. Incidence and severity of Zoster and PHN increase with age, and may be so severe as to profoundly reduce quality of life. As such, PHN remains a pressing public health concern. The mechanisms by which VZV causes prolonged pain are not understood. In response to FOA PA-13-118, we expand a pre-clinical model of PHN, where VZV inoculated into the rat footpad induces prolonged signs of pain that mirror aspects of human PHN. We have now expanded the model to show pain develops from VZV placed at the whisker pad and trigeminal ganglia. We propose that our study of these models will enable us to gain comprehension of how VZV interacts with the nervous system to induce pain, and test improved treatments. In Aim 1, we will define what is needed to be made by VZV in the rat leading to pain. We will test the hypothesis that a limited VZV expression program is sufficient without need for productive replication. This may reflect human ganglia after zoster, in which viral expression without full replication triggers changes leading t chronic pain. PHN is notoriously unresponsive to antivirals. We will focus on mechanisms by which the VZV IE62 regulatory protein drives pain: IE62 is found in ganglionic neurons of rats with pain. Third, we will investigate why VZV lacking the ORF47 kinase does not induce chronic pain, testing the hypothesis that ORF47 is needed to initiate neuronal infection. Aim 2 will determine if pain is transmitted only by VZV infected and VZV protein-expressing neurons, or includes neurons altered by processes other than VZV infection or viral protein expression. We will exploit an innovative ligand-dependent glycine receptor expression-based system to stop firing of neurons in which receptor is expressed. We will then address what neuron subtypes signal chronic pain induced by the IE62 protein, using neuron-specific promoters in replication defective HSV (rdHSV) vectors. Aim 3 will seek to improve and more effectively treat the VZV-induced pain state in the rat, by seeking to transcriptionally target specific neuron populations with rdHSV vectors that reduce pain. This may not only provide longer or more specific relief of VZV-induced pain, but will provide information on types of neurons inducing pain. Together, our approaches have potential to revolutionize the way we think about VZV induced pain, which can be then applied to those with zoster unfortunate to suffer PHN and its consequences.